In the past 30 years, the mortality rate of lung cancer has risen by 465%, and the incidence rate has increased by 26.9% annually. It has become the first cause of death from malignant tumors in China. Among them, non-small cell lung cancer (NSCLC) accounts for greater than 80% of all lung cancers. Only one third of NSCLC patients have the opportunity of surgical treatment, and about 70% of patients have been locally advanced or had distant metastasis before seeing a doctor, and lost the chance of surgery. In this case, drug treatment seems particularly important. The anaplastic lymphoma kinase (ALK) gene fusion has recently become an important biomarker, which helps the identification of patients with specific NSCLC subgroup and thereby the choice of the corresponding inhibitors for treatment. The International Association for the Study of Lung Cancer (IASLC) recommends the use of ALK fusion testing to guide the patient screening and select from patients with advanced adenocarcinoma who can be treated with an ALK inhibitor regardless of gender, race, smoking history, or other clinical risk factors. Fluorescence in situ hybridization (FISH) using a dual-label separation probe is used for the selection of patients who can receive ALK-TKI therapy. This diagnostic method was approved by the US FDA and has been adopted in the study of the treatment of ALK rearranged tumors with crizotinib. Crizotinib is an oral adenosine triphosphate (ATP) competitive inhibitor that can inhibit ALK and MET tyrosine kinases and also inhibit the activity of ROS1 and RON kinase.
However, crizotinib has the following side effects: visual disturbances, gastrointestinal side effects, and 3-4 level of hepatic aminotransferase increase in 16% of cases. In addition, ALK-positive patients inevitably acquired resistance after a sensitive period of crizotinib treatment at the initial stage. Thus, there is a need to develop compounds that have ALK kinase inhibitory activity and/or have better pharmacodynamic/pharmacokinetic properties.